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Catecholamine effects on cardiac remodelling, oxidative stress and fibrosis in experimental heart failure
Dominique Bonnefont-Rousselot1, Allal Mahmoudi, Nathalie Mougenot
1Laboratoire de Biochimie B, Coeur et Vaisseaux, Groupe Hospitalier Pitié-Salpêtrière (AP-HP), 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. dominique.rousselot@psl.ap-hop-paris.fr
Insights
Noradrenaline infusion after heart attack in rats increased cardiac fibrosis and hypertrophy without worsening oxidative stress. This suggests catecholamines may promote fibrosis through mechanisms beyond oxidative damage.
Area of Science:
- Cardiovascular Research
- Pathophysiology
- Molecular Cardiology
Background:
- Heart failure is characterized by cardiac remodeling and fibrosis.
- Oxidative stress plays a role in the progression of heart disease.
- Adrenergic stimulation is a key factor in cardiac response to injury.
Purpose of the Study:
- To investigate the relationship between oxidative stress, cardiac remodeling, and fibrosis.
- To assess the effects of adrenergic stimulation (noradrenaline) on an experimental model of heart failure.
- To determine if elevated catecholamine levels exacerbate cardiac damage post-myocardial infarction.
Main Methods:
- Induction of large myocardial infarction in Wistar rats via coronary artery ligation.
- Sham surgery control group.
- Chronic administration of noradrenaline via osmotic pumps for 2 weeks post-surgery.
- Assessment of hemodynamics, cardiac morphology, fibrosis, catecholamine levels, and oxidative stress markers.
Main Results:
- Myocardial infarction led to left ventricle dilation, right ventricle hypertrophy, and increased collagen deposition and oxidative stress in non-infarcted areas.
- Chronic noradrenaline administration induced hypertrophy and inotropic stimulation, but less pronounced in infarcted rats compared to sham rats.
- Noradrenaline infusion at elevated levels was associated with increased fibrosis and oxidative stress, with additional fibrosis in infarcted animals without further oxidative stress increase.
Conclusions:
- Noradrenaline infusion, at levels exceeding post-infarction physiological ranges, is linked to cardiac fibrosis and oxidative stress.
- In infarcted hearts, noradrenaline promotes further fibrosis independently of increasing oxidative stress.
- Catecholamine-induced fibrosis may involve mechanisms like ischemia, mechanical stress, and inflammatory pathways, not solely oxidative stress.
Abstract:
The aim of the study was to assess the relationships between oxidative stress, cardiac remodelling and fibrosis on an experimental model of heart failure with adrenergic stimulation. Large myocardial infarction (approximately 50% of the left ventricle myocardium) was obtained by ligation of the left coronary artery of normotensive male Wistar rats. Sham animals were submitted to left thoracotomy without coronary ligation. In order to perform cardiac stimulation by catecholamines, mini-osmotic pumps were implanted in animals 10 weeks after surgery to deliver noradrenalin for a 2-week period. At the end of this period, the following investigations were performed: haemodynamics, morphometry, fibrosis quantification, plasma and tissue catecholamine assay and oxidative stress status. Coronary ligation induced dilatation of left ventricle with compensatory hypertrophy of the right ventricle and of the remaining left ventricle myocardium. This remodelling process was associated in non-infarcted myocardium with increased collagen infiltration and increased oxidative stress. Ten weeks after surgery, the chronic administration of noradrenalin for 2 weeks did not increase oxidative stress. Noradrenalin, however, induced inotropic stimulation and myocardial hypertrophy, but to a lesser extent in infarcted rats compared to sham rats. Our results suggest that noradrenalin infusion to levels in excess of those seen post-infarction is associated with fibrosis and oxidative stress. Moreover, noradrenalin in infarcted animals caused additional fibrosis without further increasing oxidative stress. The mechanism of catecholamine-induced fibrosis may thus involve different processes such as ischaemia, increased mechanical stress, cytokines and neurohormones.